Prenatal alcohol exposure (PAE) of the fetus may result in physiognomic alterations and/or impediment of cognitive development, summarized as fetal alcohol spectrum disorders (FASDs). Although alcohol is metabolized in the liver, the effects of PAE on the fetal liver are unknown. For this study, n = 21 prenatal MRIs of fetuses with PAE and n = 45 MRIs of fetuses without PAE were included. To assess macroscopic organ development, liver volumetry was conducted and compared to an established prenatal estimation formula. A texture-based radiomics analysis based on ensemble (random forest) and linear (L2-penalized logistic regression) models was conducted. PAE and non-PAE fetuses were age-matched (gestational age 27.4 [IQR 25.1–30.0] vs. 26.7 [25.4–29.3] weeks, p = 0.650). PAE had no effect on liver volume (normalized per gestational week, p = 0.971) or signal intensity (SI) in T1 (p = 0.574) and T2 (p = 0.104). MRI-derived liver volumetry correlated strongly with a gestational age-based volume estimation regardless of PAE (both r > 0.75, p < 0.001). A texture-based radiomics analysis was unable to discern between PAE and no-PAE fetuses (ROC-AUC = 0.43, 95

To compare prenatal imaging-based subjective assessment of the ganglionic eminence (GE) on fetal MRI with three-dimensional volumetric analysis in patients with structural central nervous system anomalies. This retrospective study investigated 17 fetuses (undergoing 20 fetal MRIs, mean gestational age 26.3 weeks, SD 3.3, range 21.7–33.4 weeks) with enlarged GE based on subjective assessment of fetal neuroimaging experts and concurrent structural brain anomalies. Three-dimensional volumetry of super-resolution MRI was performed and compared to age-matched neurotypical controls (94 fetuses, 100 MRIs, mean age 27.2 weeks, SD 3.6, range 21.7–34.0 weeks). Among 20 MR examinations, in only 5 cases (25

BACKGROUND AND PURPOSE:The superficial subplate forms the interface between the cortical plate and the deeper subplate, as a transient sublamina prominent during midfetal development of the human brains when many cortical malformations originate, and prenatal counselling is needed. Our aim was to assess the visibility of the superficial subplate throughout development using in vivo 3 Tesla fetal MR images in the human brain. MATERIAL AND METHODS:In this retrospective observational study, 51 human fetuses (19- 36 gestational weeks, GW) medically assessed as neurotypical were imaged on a 3 Tesla MR scanner in vivo, using single shot, fast spin-echo T2-weighted sequences (T2-weighted SSFSE) and images in three planes were selected. Three readers twice assessed the visibility of the sSP on the selected images in the region of frontal, parietal, temporal, and occipital lobes. To explore the relationship between the visibility of the superficial subplate (sSP) and gestational age, regression analysis was used. A quadratic model was applied to investigate the non-linear association between visibility scores and fetal age. The inter-observer agreement on the visibility of sSP was scrutinized both pairwise and among all three raters. Weighted kappa statistics determined inter- and intra-rater agreement. RESULTS:The visualization of the sSP on in vivo fetal 3T MRI was possible between the 19th and 27th weeks of gestation, in one or more lobes, (the frontal, parietal, temporal, occipital), with optimal visibility between 20 and 27 gestational weeks coinciding with the peaks in glycosaminoglycan expression in the sSP. Inter-rater agreement ranged from moderate to excellent (weighted κ = 0.57-0.93), with a mean κ of 0.81 ± 0.10 on first assessment, improving to 0.88 ± 0.03 on second assessment. Intra-rater agreement was good to excellent (κ = 0.75-0.90). CONCLUSIONS:The superficial subplate is visible on T2-w in vivo fetal MRI at 3T. A deeper understanding of the in vivo appearance of the laminar organization of the human fetal brain, including the superficial subplate, is required to accurately interpret altered fetal brain development, thereby improving early diagnostic accuracy, reducing false-positive assessments, and supporting prenatal counselling in cases of suspected cortical malformations.

BACKGROUND AND PURPOSE:Subpial hemorrhage (SPH) is a rare form of intracranial hemorrhage, typically observed in neonates. It differs from subarachnoid and subdural hemorrhages in both anatomic location and underlying pathophysiology. The primary aim of this study was to describe the distinct fetal MRI features of cerebellar SPH. MATERIALS AND METHODS:This retrospective multicenter study included 24 fetuses, aged between 20 + 5 and 34 + 0 weeks of gestation, from 3 institutions. Postmortem 3T MRI and neuropathologic work-up were available for 4 cases and 1 postnatal MRI. RESULTS:SPH was located infratentorially along the cerebellum and vermis in all 24 cases. SPH was observed as either unilateral, bilateral, or multifocal, with several distinct morphologic patterns, crescentic or spherical/punctate shapes along the cerebellar surface. Postmortem MRI in one case confirmed the prenatal MRI findings, and neuropathological analysis confirmed SPH extending from the pia-arachnoid through the molecular layer and hemosiderin-containing macrophages within the external granular layer associated with reduced and disrupted Bergmann glial processes in areas adjacent to SPH. CONCLUSIONS:Fetal cerebellar SPHs are characterized by crescentic foci of signal abnormality that appear "attached" to the cerebellar surface. Cerebellar SPH constitutes a distinct entity that may be detected on prenatal imaging, either in isolation or in association with fetal germinal matrix-intraventricular hemorrhage.

OBJECTIVE:Trisomy 21 (T21) is associated with various neurological impairments. However, the mechanisms of fetal brain development in T21 and their impact on neurodevelopmental outcomes remain unclear, limiting prenatal counseling. Therefore, this study aims to assess neuropathological changes in fetuses with T21 and the associated neurodevelopmental outcome. METHOD:This was a case-control study comparing brain patterns in neurosonography and MRI of fetuses with T21 to healthy controls. Additionally, neurodevelopmental outcome was assessed prospectively. Thereby, an outcome score was calculated to identify brain patterns linked to unfavorable neurodevelopmental outcomes. RESULTS:108 fetuses were included consisting of 54 fetuses with T21 and 54 controls. In the study group, significantly more fetal brain abnormalities were found compared to the control group (p < 0.001). Brain abnormalities in T21 most commonly included ventriculomegaly (24.1%), cerebellar hypoplasia (22.2%) and widening of subarachnoid fluid spaces (20.4%). Although the neurodevelopmental score showed no significant differences based on the presence of brain abnormalities, fetuses with widened subarachnoid fluid spaces or cerebellar hypoplasia were solely associated with an unfavorable outcome score. CONCLUSION:Fetuses with T21 show significantly more brain abnormalities compared with healthy controls, which should be considered for prenatal counseling. Some specific brain abnormalities were demonstrated only in the group with poorer neurodevelopmental outcomes, such as cerebellar hypoplasia and widened subarachnoid fluid spaces. However, the exploratory nature of the analysis must be considered, and additional studies are highly needed.

CHARGE syndrome (CS) and trisomy 13 (T13) and 18 (T18) are heterogeneous diseases with overlapping morphological features. Historically, T13 and T18 were deemed incompatible with life. Recently, numerous studies have reported prolonged survival for some affected patients. Consequently, the question of individual counseling has arisen. This study aimed to analyze the fetal MRI-based phenome of CS, T13, and T18. Fetal MRI-based phenotyping was conducted, and a morphological disease severity score that assessed 16 anatomical regions was proposed. Furthermore, a co-occurrence analysis was generated to visualize the overlapping and differentiating features of CS, T13, and T18. Forty-eight fetuses who underwent fifty-seven fetal MRI scans were analyzed. Disease severity scores ranged from 1-25 (mean 12.7) and highlighted heterogeneous disease manifestations among investigated patients. In the co-occurrence analysis the T13 network showed the highest complexity. Considering recent trends towards a change in management from mostly palliative to therapeutic care for patients with CS, T13, and T18, care providers face challenging decisions regarding management. The proposed preliminary MRI-based phenotyping score and the provided phenome visualization aim to aid physicians in counseling and choosing appropriate management plans. Future studies will be necessary to correlate prenatal imaging findings to outcome data in larger patient collectives. Question What are the phenotypical presentations of CHARGE syndrome, trisomy 13, and trisomy 18 in fetal MRI and can prenatal MRI findings help clinicians in predicting postnatal outcomes? Findings MRI phenomes were visualized in co-occurrence networks, and a preliminary disease severity score was proposed, based on available outcome data, to aid in risk stratification. Clinical relevance Recent trends in management, a shift from mostly palliative to therapeutic care for affected patients, have challenged clinicians. The provided phenome visualization of these heterogeneous diseases and the proposed disease severity score may aid physicians in counseling and selecting appropriate pregnancy management.

To provide initial insights into structural placental anomalies following prenatal alcohol exposure (PAE) utilizing routine human fetal MRI. This retrospective study investigated 29 fetuses (mean gestational age 26.1 weeks, SD 3.7 weeks) subjected to PAE (PAE+) without confounding comorbidities and 29 age-matched controls without PAE (PAE−). Assessment of the placenta was performed using 1.5- and 3-T fetal MRI scans and included analysis of twelve structural parameters. This study provides the first data on in vivo fetal MRI results regarding the effects of PAE on placenta structure. We identified an association of PAE with increased occurrence rates of placental lobulation, venous congestion, any type of placental hematoma, subamniotic hematoma on the placental surface, specifically, and hypercoiled umbilical cord. A trend was observed with increased placental lobulation occurring at earlier gestational ages in PAE+ patients. Overall, more structural placental anomalies were detected in women with PAE compared to unexposed controls, despite a relatively low amount of alcohol consumption (1–3 drinks per week) within the exposed group. Early detection of PAE is essential, considering the potentially detrimental effects of ethanol on placental structure. Fetal MRI provides a complementary tool for ultrasound-based assessment of fetus and placenta, not only in cases with congenital disorders, but also to assess effects of epigenetic factors such as PAE. Question To assess the presence of structural placental anomalies in patients with PAE and unexposed controls in fetal MRI. Findings PAE is associated with increased occurrence rates of placental abnormalities - regarding the total number and type of structural anomalies. Clinical relevance Fetal MRI provides a complementary tool to ultrasound to assess the placenta. Early detection of structural placental anomalies, which were found to occur more frequently in alcohol exposed fetuses, may aid counseling physicians in choosing appropriate pregnancy management plans.

The organization of the human cerebral cortex during fetal development is regulated by multiple processes, including neurogenesis and neuronal migration, which are essential for cortical expansion and folding patterns. According to the radial unit hypothesis, neurons originate in the germinal zone and migrate radially along the radial glial scaffolds to reach the cortical plate. However, the spatial distributions of these scaffolds and their roles in cortical folding remain unclear. Consequently, a computational model was developed to simulate virtual scaffolds extending from the cerebral ventricular surface to the white matter, incorporating region-specific neurogenic potential. The results demonstrate dense scaffold distribution in the perisylvian region, where complex cortical folding emerges, suggesting that differences in scaffold distribution contribute to region-specific cortical expansion. Notably, increased neuron influx along the scaffolds in the perisylvian region may contribute to early volumetric growth, potentially influencing Sylvian fissure formation. These findings align with previous reports that demonstrate distinct developmental patterns in this region. Being an accurate representation of radial migration pathways, this model provides a framework for integrating tangential migration of inhibitory neurons, refining scaffold distribution estimates, and quantifying early cortical development, offering insights into neurogenetic regional variations, scaffold architecture, and cortical folding in the human fetal brain.

Irregular and unpredictable fetal movement is the most common cause of artifacts in in utero functional magnetic resonance imaging (fMRI), affecting analysis and limiting our understanding of early functional brain development. The accurate detection of corrupted functional connectivity (FC) resulting from motion artifacts or preprocessing, instead of neural activity, is a prerequisite for reliable and valid analysis of FC and early brain development. Approaches to address this problem in adult data are of limited utility in fetal fMRI. In this study, we evaluate a novel technique for robust computational assessment of motion artifacts, and the quantitative comparison of regression models for artifact removal in fetal FC analysis. It exploits the association between dynamic FC and non-stationarity of fetal movement, to detect residual noise. To validate our motion artifact detection technique in detail, we used a parametric generative model for neural events and fMRI blood oxygenation level-dependent (BOLD) signal. We conducted a systematic evaluation of 11 commonly used regression models in a sample of 70 fetuses with gestational age of 19-39 weeks. Results demonstrate that the proposed method has better accuracy in identifying corrupted FC compared to methods designed for adults. The technique, suggests that censoring, global signal regression and anatomical component-based regression models are the most effective models for compensating motion. The benchmarking technique, and the generative model for realistic fetal fMRI BOLD enables investigators conducting in utero fMRI analysis to effectively quantify the impact of fetal motion and evaluate alternative regression strategies for mitigating this impact. The code is publicly available at: https://github.com/cirmuw/fetalfMRIproc.

ABSTRACTObjectiveTo apply a network medicine‐based approach to analyze the phenome of the prenatal fetal MRI and biometric findings in the Chiari II malformation (CM II) to detect specific patterns and co‐occurrences.MethodA single‐center retrospective review of fetal MRI scans obtained in fetuses with CM II was performed. Co‐occurrence analysis was utilized to generate a phenotypic comorbidity matrix and visualized by Gephi software. Traditional univariate regression and geometric thin‐plate spline methodology were used to elucidate the mechanisms underlying the relationships between morphometric measurements and geometric landmarks of the spine, skull, and brain deformations.ResultsThe CM II phenome consists of 35 nodes interconnected by 979 edges with a density of 0.828. Key “hubs” identified within this network include spinal bony defects, reduced posterior fossa dimensions, and vermis ectopia. The brain edema phenotype appearing only in the fetal stage but disappearing after postnatal surgery, links to increased postnatal morbidity and demonstrates distinct shape patterns by geometric analysis. Traditional univariate regression reveals correlations among spinal defects, posterior fossa dimensions, and caudal extent of vermis ectopia. The degree of brain rearrangement versus spinal bony rearrangement shows a correlation (r = 0.721, p = 0.0023) by partial least‐squares analysis.ConclusionThe CM II prenatal phenome is a multifaceted network centered around three key elements—spinal bony defects, small posterior fossa, and vermis ectopia—with strong interconnections. Fetal brain edema emerged as an exclusively prenatally detectable and transient phenotype of prognostic relevance.

PURPOSE:To quantify hepatocellular lipids in the fetal liver, we tested the feasibility of the multiecho mDixon Quant sequence (chemical shift encoded magnetic resonance imaging (MRI)) during clinically routine fetal whole-body MRI and investigated the correlation of hepatocellular lipids with different clinical maternal and fetal parameters. METHODS:The livers of 155 fetuses were prospectively investigated with multiecho CSE-MRI sequences during clinically indicated whole-body MRI, performed between gestational weeks 19 and 38 on a 1.5 Tesla scanner. The hepatocellular lipids were quantified by measuring the proton density fat fraction in the left and right liver lobe. Results of the right liver lobe were correlated with the maternal body mass index, maternal age, presence of maternal diabetes, gestational age at assessment, estimated fetal weight, fetal sex, and birth weight. RESULTS:Quantification of fetal hepatocellular lipids was feasible in 151/155 (97.4 %) fetuses. Four examinations were excluded due to strong motion artifacts and poor image quality. The proton density fat fraction values ranged from 0 % to 5.7 % (mean 2.26; SD 1.37). Hepatocellular lipids were associated with the presence of maternal diabetes (p = 0.027). No association was found between hepatocellular lipids and maternal body mass index (p = 0.306), maternal age (p = 0.582), gestational age (p = 0.456), estimated fetal weight (p = 0.176), fetal sex (p = 0.181), or birth weight (p = 0.957). CONCLUSION:Quantification of fetal hepatocellular lipids is feasible and may routinely be performed during whole-body MRI to detect early liver fat accumulation, particularly in the presence of maternal diabetes.

Pre-surgical information about tumor consistency could facilitate neurosurgical planning. This study used multi-dynamic-multi-echo (MDME)-based relaxometry for the quantitative determination of pituitary tumor consistency, with the aim of predicting lesion resectability. Seventy-two patients with suspected pituitary adenomas, who underwent preoperative 3 T MRI between January 2020 and January 2022, were included in this prospective study. Lesion-specific T1-/T2-relaxation times (T1R/T2R) and proton density (PD) metrics were determined. During surgery, data about tumor resectability were collected. A Receiver Operating Characteristic (ROC) curve analysis was performed to investigate the diagnostic performance (sensitivity/specificity) for discriminating between easy- and hard-to-remove by aspiration (eRAsp and hRAsp) lesions. A Mann-Whitney-U-test was done for group comparison. A total of 65 participants (mean age, 54 years ± 15, 33 women) were enrolled in the quantitative analysis. Twenty-four lesions were classified as hRAsp, while 41 lesions were assessed as eRAsp. There were significant differences in T1R (hRAsp: 1221.0 ms ± 211.9; eRAsp: 1500.2 ms ± 496.4; p = 0.003) and T2R (hRAsp: 88.8 ms ± 14.5; eRAsp: 137.2 ms ± 166.6; p = 0.03) between both groups. The ROC analysis revealed an area under the curve of 0.72 (95

Objectives: This retrospective study aimed to identify quantitative magnetic resonance imaging markers in the brainstem of preterm neonates with intraventricular hemorrhages. It delves into the intricate associations between quantitative brainstem magnetic resonance imaging metrics and neurodevelopmental outcomes in preterm infants with intraventricular hemorrhage, aiming to elucidate potential relationships and their clinical implications. Materials and methods: Neuroimaging was performed on preterm neonates with intraventricular hemorrhage using a multi-dynamic multi-echo sequence to determine T1 relaxation time, T2 relaxation time, and proton density in specific brainstem regions. Neonatal outcome scores were collected using the Bayley Scales of Infant and Toddler Development. Statistical analysis aimed to explore potential correlations between magnetic resonance imaging metrics and neurodevelopmental outcomes. Results: Sixty preterm neonates (mean gestational age at birth 26.26 +/- 2.69 wk; n = 24 [40%] females) were included. The T2 relaxation time of the midbrain exhibited significant positive correlations with cognitive (r = 0.538, P < 0.0001, Pearson's correlation), motor (r = 0.530, P < 0.0001), and language (r = 0.449, P = 0.0008) composite scores at 1 yr of age. Conclusion: Quantitative magnetic resonance imaging can provide valuable insights into neurodevelopmental outcomes after intraventricular hemorrhage, potentially aiding in identifying at-risk neonates. Multi-dynamic multi-echo sequence sequences hold promise as an adjunct to conventional sequences, enhancing the sensitivity of neonatal magnetic resonance neuroimaging and supporting clinical decision-making for these vulnerable patients.

INTRODUCTION:This study aimed to assess the visibility of the indusium griseum (IG) in magnetic resonance (MR) scans of the human fetal brain and to evaluate its reliability as an imaging biomarker of the normality of brain midline development. MATERIAL AND METHODS:The retrospective observational study encompassed T2-w 3T MR images from 90 post-mortem fetal brains and immunohistochemical sections from 41 fetal brains (16-40 gestational weeks) without cerebral pathology. Three raters independently inspected and evaluated the visibility of IG in post-mortem and in vivo MR scans. Weighted kappa statistics and regression analysis were used to determine inter- and intra-rater agreement and the type and strength of the association of IG visibility with gestational age. RESULTS:The visibility of the IG was the highest between the 25 and 30 gestational week period, with a very good inter-rater variability (kappa 0.623-0.709) and excellent intra-rater variability (kappa 0.81-0.93). The immunochemical analysis of the histoarchitecture of IG discloses the expression of highly hydrated extracellular molecules in IG as the substrate of higher signal intensity and best visibility of IG during the mid-fetal period. CONCLUSIONS:The knowledge of developmental brain histology and fetal age allows us to predict the IG-visibility in magnetic resonance imaging (MRI) and use it as a biomarker to evaluate the morphogenesis of the brain midline. As a biomarker, IG is significant for post-mortem pathological examination by MRI. Therefore, in the clinical in vivo imaging examination, IG should be anticipated when an assessment of the brain midline structures is needed in mid-gestation, including corpus callosum thickness measurements.

To identify brain edema in fetuses with Chiari II malformation using a multiparametric approach including structural T2-weighted, diffusion tensor imaging (DTI) metrics, and MRI-based radiomics. A single-center retrospective review of MRI scans obtained in fetuses with Chiari II was performed. Brain edema cases were radiologically identified using the following MR criteria: brain parenchymal T2 prolongation, blurring of lamination, and effacement of external CSF spaces. Fractional anisotropy (FA) values were calculated from regions of interest (ROI), including hemispheric parenchyma, internal capsule, and corticospinal tract, and compared group-wise. After 1:1 age matching and manual single-slice 2D segmentation of the fetal brain parenchyma using ITK-Snap, radiomics features were extracted using pyradiomics. Areas under the curve (AUCs) of the features regarding discriminating subgroups were calculated. Ninety-one fetuses with Chiari II underwent a total of 101 MRI scans at a median gestational age of 24.4 weeks and were included. Fifty scans were visually classified as Chiari II with brain edema group and showed significantly reduced external CSF spaces compared to the nonedema group (9.8 vs. 18.3 mm, p < 0.001). FA values of all used ROIs were elevated in the edema group (p < 0.001 for all ROIs). The 10 most important radiomics features showed an AUC of 0.81 (95

Mutations in ARID1B, a member of the mSWI/SNF complex, cause severe neurodevelopmental phenotypes with elusive mechanisms in humans. The most common structural abnormality in the brain of ARID1B patients is agenesis of the corpus callosum (ACC), characterized by the absence of an interhemispheric white matter tract that connects distant cortical regions. Here, we find that neurons expressing SATB2, a determinant of callosal projection neuron (CPN) identity, show impaired maturation in ARID1B+/- neural organoids. Molecularly, a reduction in chromatin accessibility of genomic regions targeted by TCF-like, NFI-like, and ARID-like transcription factors drives the differential expression of genes required for corpus callosum (CC) development. Through an in vitro model of the CC tract, we demonstrate that this transcriptional dysregulation impairs the formation of long-range axonal projections, causing structural underconnectivity. Our study uncovers new functions of the mSWI/SNF during human corticogenesis, identifying cell-autonomous axonogenesis defects in SATB2+ neurons as a cause of ACC in ARID1B patients.

BACKGROUND AND PURPOSE:The radiologic evaluation of ongoing myelination is currently limited prenatally. Novel quantitative MR imaging modalities provide relaxometric properties that are linked to myelinogenesis. In this retrospective postmortem imaging study, the capability of Synthetic MR imaging and MR fingerprinting-derived relaxometry for tracking fetal myelin development was investigated. Moreover, the consistency of results for both MR approaches was analyzed. MATERIALS AND METHODS:In 26 cases, quantitative postmortem fetal brain MR data were available (gestational age range, 15 + 1 to 32 + 1; female/male ratio, 14/12). Relaxometric measurements (T1-/T2-relexation times) were determined in the medulla oblongata and the midbrain using Synthetic MR imaging/MR fingerprinting-specific postprocessing procedures (Synthetic MR imaging and MR Robust Quantitative Tool for MR fingerprinting). The Pearson correlations were applied to detect relationships between T1-relaxation times/T2-relaxation times metrics and gestational age at MR imaging. Intraclass correlation coefficients were calculated to assess the consistency of the results provided by both modalities. RESULTS:Both modalities provided quantitative data that revealed negative correlations with gestational age at MR imaging: Synthetic MR imaging-derived relaxation times (medulla oblongata [r = -0.459; P = .021]; midbrain [r = -0.413; P = .040]), T2-relaxation times (medulla oblongata [r = -0.625; P < .001]; midbrain [r = -0.571; P = .003]), and MR fingerprinting-derived T1-relaxation times (medulla oblongata [r = -0.433; P = .035]; midbrain [r = -0.386; P = .062]), and T2-relaxation times (medulla oblongata [r =-0.883; P < .001]; midbrain [r = -0.890; P < .001]).The intraclass correlation coefficient analysis for result consistency between both MR approaches ranged between 0.661 (95% CI, 0.351-0.841) (T2-relaxation times: medulla oblongata) and 0.920 (95% CI, 0.82-0.965) (T1-relaxation times: midbrain). CONCLUSIONS:There is a good-to-excellent consistency between postmortem Synthetic MR imaging and MR fingerprinting myelin quantifications in fetal brains older than 15 + 1 gestational age. The strong correlations between quantitative myelin metrics and gestational age indicate the potential of quantitative MR imaging to identify delayed or abnormal states of myelination at prenatal stages of cerebral development.